rs763428520
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2
The NM_052874.5(STX1B):āc.845T>Cā(p.Ile282Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000958 in 1,461,350 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 31)
Exomes š: 0.0000096 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
STX1B
NM_052874.5 missense
NM_052874.5 missense
Scores
5
10
4
Clinical Significance
Conservation
PhyloP100: 7.10
Genes affected
STX1B (HGNC:18539): (syntaxin 1B) The protein encoded by this gene belongs to a family of proteins thought to play a role in the exocytosis of synaptic vesicles. Vesicle exocytosis releases vesicular contents and is important to various cellular functions. For instance, the secretion of transmitters from neurons plays an important role in synaptic transmission. After exocytosis, the membrane and proteins from the vesicle are retrieved from the plasma membrane through the process of endocytosis. Mutations in this gene have been identified as one cause of fever-associated epilepsy syndromes. A possible link between this gene and Parkinson's disease has also been suggested. [provided by RefSeq, Jan 2015]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), STX1B. . Gene score misZ 2.9426 (greater than the threshold 3.09). Trascript score misZ 3.6025 (greater than threshold 3.09). GenCC has associacion of gene with generalized epilepsy with febrile seizures plus, generalized epilepsy with febrile seizures plus, type 9.
BS2
High AC in GnomAdExome4 at 14 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
STX1B | NM_052874.5 | c.845T>C | p.Ile282Thr | missense_variant | 10/10 | ENST00000215095.11 | NP_443106.1 | |
STX1B | XM_017022893.2 | c.827T>C | p.Ile276Thr | missense_variant | 10/10 | XP_016878382.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
STX1B | ENST00000215095.11 | c.845T>C | p.Ile282Thr | missense_variant | 10/10 | 1 | NM_052874.5 | ENSP00000215095.5 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152032Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000120 AC: 3AN: 249946Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135348
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GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461350Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6AN XY: 726976
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GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000658 AC: 1AN: 152032Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74274
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Data not reliable, filtered out with message: AS_VQSR
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:6Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Generalized epilepsy with febrile seizures plus, type 9 Pathogenic:1Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Oct 30, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | research | Pediatrics, MediClubGeorgia | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 25, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Aug 24, 2022 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 18, 2024 | Apparently de novo variant in a patient with developmental and epileptic encephalopathy in published literature (PMID: 30737342); Observed in an individual referred for genetic testing at GeneDx who also had a different genetic etiology for the phenotype; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 35350397, 37066095, 35982159, 33057194, 30737342) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | May 27, 2022 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 19, 2022 | The c.845T>C (p.I282T) alteration is located in coding exon 10 of the STX1B gene. This alteration results from a T to C substitution at nucleotide position 845, causing the isoleucine (I) at amino acid position 282 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
STX1B-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 26, 2024 | The STX1B c.845T>C variant is predicted to result in the amino acid substitution p.Ile282Thr. This variant was reported de novo in an individual with STX1B-related disease (Wolking et al. 2019. PubMed ID: 30737342). This variant is reported in 0.0027% of alleles in individuals of European (Non-Finnish) descent in gnomAD, and It has conflicting interpretations in ClinVar, including likely benign and uncertain significance. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Uncertain
D
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
N
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
B
Vest4
MutPred
Loss of stability (P = 0.0089);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at